Selective cyclic peptides with melanocortin-4 receptor (MC4-R) agonist activity

a cyclic peptide and melanocortin-4 receptor technology, applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems of increasing the risk of skin cancer, adrenal cancer, and significant burden on the health care system

Inactive Publication Date: 2006-05-16
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone.
Agonism of the MC1-R receptor results in stimulation of the melanocytes which causes eumelanin and increases the risk for cancer of the skin.
Stimulation of MC2-R activity can result in carcinoma of adrenal tissue.
Because of their different functions, simultaneous agonism of the activities of multiple melanocortin receptors has the potential of causing unwanted side effects.

Method used

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  • Selective cyclic peptides with melanocortin-4 receptor (MC4-R) agonist activity
  • Selective cyclic peptides with melanocortin-4 receptor (MC4-R) agonist activity
  • Selective cyclic peptides with melanocortin-4 receptor (MC4-R) agonist activity

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Fmoc-1-amino-4-phenylcyclohexane-1-carboxylic acid (Fmoc-Apc)

[0122]Step 1:

[0123]To a solution of 4-phenylcyclohexanone (10.0 g, 57.5 mmol) in ethanol (100 mL) and water (33 mL) in a glass pressure bottle, were added ammonium carbonate (33 g, 344 mmol, 6 equiv.) and potassium cyanide (5.6 g, 86.2 mmol, 1.5 equiv.). The mixture was heated at 80-90° C. for 24 hrs. The cooled reaction mixture was added to icy water (400 ml) and stirred vigorously for 30 min. The resulting precipitate was suction filtered, washed thoroughly with water and dried to yield the hydantoin A as a white solid (14.0 g, 100% yield). 1H NMR (DMSO-d6): 8.63 (s, 1H), 7.23-7.36 (m, 4), 7.15 (m, 1), 2.50 (m, 1H), 2.10 (m, 1H), 1.85 (d, 1H) and 1.55-1.80 (m, 6H).

Step 2:

[0124]The hydantoin A (10.0 g) was suspended in aqueous NaOH (6N, 350 mL) and heated at 130° C. for 2-3 days. Upon the completion of the hydrolysis, the reaction mixture was neutralized with conc. HCl to slightly acidic (pH˜6). The resul...

example 2

Preparation of Fmoc-1-amino4-(4-methoxyphenyl)cyclohexane-1-carboxylic acid (Fmoc-4-MeOApc-OH)

[0126]Step 1:

[0127]A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodomethane (4.9 mL, 11.2 g, 78.6 mmol, 3 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-methoxyphenyl)-cyclohexanone (5.34 g, 100%). 1H NMR(CDCl3) 7.16 (dt, 2H), 6.87 (dt, 2H), 3.78 (s, 3H), 2.99 (tt, 1H), 2.47-2.53 (m, 4H), 2.20 (m, 2H) and 1.83-1.98 (m, 2H); MS (electrospray) m / e, 205 (M+1)+, Calcd for C13H16O2, 204.

Step 2:

[0128]To a solution of the 4-(4-methoxyphenyl)-cyclohexanone (3.86 g, 18.9 mmol) in ethanol (50 mL) and water (15 mL) in a glass pressure bottle, were added ammonium carbona...

example 3

Preparation of Fmoc-1-amino-4-(4-ethoxyphenyl)cyclohexane-1-carboxylic acid (Fmoc-4-EtOApc-OH)

[0131]Step 1:

[0132]A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodoethane (10.5 mL, 20.5 g, 131 mmol, 5 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-ethoxyphenyl)-cyclohexanone (5.74 g, 100%). 1H NMR (CDCl3) 7.15 (dt, 2H), 6.86 (dt, 2H), 4.02 (q, 2H), 2.99 (tt, 1H), 2.46-2.54 (m, 4H), 2.16-2.24 (m, 2H), 1.83-2.00 (m, 2H) and 1.41 (t, 3H); MS (electrospray) m / e, 219 (M+1)+, Calcd for C14H18O2, 218.

Step 2:

[0133]To a solution of the 4-(4-ethoxyphenyl)-cyclohexanone (4.15 g, 19.01 mmol) in ethanol (50 mL) and water (15 mL) in a glass pressure bottle, were adde...

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Abstract

Peptides cyclized via disulfide or lactam bridges are disclosed. The peptides exhibit melanocortin-4 receptor agonist activity and are useful for treating obesity.

Description

PRIORITY TO PROVISIONAL APPLICATION(S) UNDER 35 U.S.C. § 119(E)[0001]This application claims priority under 35 U.S.C. § 19(e) of provisional application(s) Ser. No. 60 / 229,184, filed Aug. 30, 2000.BACKGROUND OF THE INVENTION[0002]Obesity is widely recognized as a serious health problem for the developed countries, and has reached epidemic status in the United States. More than 50% of the U.S. population is considered overweight, with >25% diagnosed as clinically obese and at considerable risk for heart disease, non-insulin dependent diabetes mellitus (NIDDM), hypertension, and certain cancers. This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone. Strategies for treating obesity include reducing food intake or enhancing the expenditure of energy.[0003]It has been demonstrated that, when injected into the third ventricle of the brain or intraperitoneally, a cyclic ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K7/50A61K38/00A61K38/12A61P3/04A61P43/00C07K7/54C07K7/56C07K14/68
CPCA61K38/00C07K7/56C07K14/68A61P3/00A61P3/04A61P43/00C07K7/64
Inventor CHEN, LICHEUNG, ADRIAN WAI-HINGCHU, XIN-JIEDANHO, WALEEDSWISTOK, JOSEPHWANG, YAOYAGALOFF, KEITH ALAN
Owner F HOFFMANN LA ROCHE & CO AG
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